Violation of purine metabolism symptoms treatment. Purine metabolism disorders in alcoholism. Etiology and pathogenesis

Acetonemic syndrome in children (AS), or the syndrome of cyclic acetonemic vomiting (non-diabetic ketosis, non-diabetic ketoacidosis, acetonemic vomiting), is a set of symptoms that are caused by an increase in the blood content of ketone bodies: acetone, acetoacetic acid and β-hydroxybutyric acid - breakdown products of fatty acids. acids and ketogenic amines.

There are primary (idiopathic) and secondary (against the background of somatic, infectious, endocrine diseases, tumors and lesions of the central nervous system) acetonemic syndrome. Of greatest interest is the primary AS, which will be discussed below.

Prevalence

AS is a disease predominantly of childhood, manifested by stereotypical repeated episodes of vomiting that alternate with periods of complete well-being. It often occurs in children during the first years of life. The prevalence of AS is poorly understood. AS affects 2.3% of Austrians, 1.9% of Scottish residents. In India, AS is responsible for 0.51% of all pediatric hospital admissions. According to Russian literature, primary AS occurs in 4-6% of children aged 1 to 13 years. More often AS is registered in girls. The median age of onset of AS is 5 years. 50% of patients with this pathology require hospitalization and intravenous fluids. The average annual cost of examination and treatment of one patient with this pathology in the United States is 17 thousand dollars.

Etiology and pathogenesis

The main factor in the background of which AS occurs is an anomaly of the constitution - neuro-arthritic diathesis (NAD). However, any stressful, toxic, alimentary, endocrine effects on energy metabolism, even in children without NAD, can cause the development of acetonemic vomiting.

Normally, the catabolic pathways of carbohydrate, protein, and fat metabolism intersect in the Krebs cycle, the universal pathway for energy supply to the body.

The starting factor for the development of ketosis is stress with a relative predominance of contrainsular hormones and nutritional disorders in the form of starvation or excessive consumption of fatty and protein foods (ketogenic amino acids) with a lack of carbohydrates. The absolute or relative lack of carbohydrates causes the stimulation of lipolysis to meet the needs of the body.

Ketosis causes a number of adverse effects on the child's body. First, with a significant increase in the level of ketone bodies, which are anion donors, metabolic acidosis occurs with an increased anion gap - ketoacidosis.

Its compensation is carried out due to hyperventilation, which leads to hypocapnia, causing vasoconstriction, including cerebral vessels. Secondly, an excess of ketone bodies has a narcotic effect on the central nervous system, up to the development of coma. Thirdly, acetone is a fat solvent and damages the lipid bilayer of cell membranes.

In addition, the utilization of ketone bodies requires an additional amount of oxygen, which can cause a mismatch between the delivery and consumption of oxygen, that is, it contributes to the development and maintenance of a pathological condition.

An excess of ketone bodies irritates the mucous membrane of the gastrointestinal tract, which is clinically manifested by vomiting and abdominal pain. The listed adverse effects of ketosis in combination with other disorders of water-electrolyte and acid-base balance (hypo-, iso- and hypertonic dehydration, metabolic acidosis due to loss of bicarbonate and / or accumulation of lactate) contribute to a more severe course of the disease, increase the length of stay in the intensive care unit therapy.

NAD is a polygenically inherited metabolic anomaly, which is based on a violation of purine metabolism with excessive production of uric acid and its precursors, instability of other types of metabolism (primarily carbohydrate and lipid) with a tendency to ketosis and mediator functions of the nervous system, which determine the features of its reactions.

The genetic factors that cause hyperuricemia include a number of enzyme defects: deficiency ofansferase; deficiency of glucose-6-phosphatase; an increase in the catalytic activity of the enzyme phosphoribosyl pyrophosphate synthetase.

The hereditary factor of purine metabolism disorders is confirmed by the results of family genetic studies of children with NAD: the frequency of detection of neuropsychiatric diseases in the pedigree of such children is up to 18%, gout is recorded in 22% of cases. In relatives of the 1st degree of kinship - urolithiasis, uric acid diathesis, metabolic arthritis occur 20 times more often than in the control group. Diseases of the circulatory system (ischemic heart disease, hypertension), diabetes mellitus are 2 times more common.

Free purines and their compounds are of particular importance in the life of the organism; the synthesis of purine bases is the central link in the biosynthesis of nucleotides, which are involved in almost all intracellular biochemical processes:

- they are activated precursors of DNA and RNA;

- nucleotide derivatives - activated intermediate products of many synthetic reactions;

- adenine nucleotide of adenosine triphosphoric acid - a universal energy "currency" in biological systems;

- adenine nucleotides - components of the three main coenzymes: NAD, FAD and COA;

- purine nucleotides play a general regulatory role in the biological activity of cells, turning into cyclic nucleotides - cyclic adenosine monophosphate and cyclic guanosine monophosphate.

In humans, the main sources of purine synthesis are phosphoribosyl monophosphate and glutamine, from which inosinic acid is formed - the main precursor of purine nucleotides, containing a fully prepared purine ring system.

From year to year, interest in the study of purine metabolism and its end product, uric acid, is growing, which is associated with a steady increase in the frequency of both asymptomatic and clinically manifest hyperuricemia, a biological anomaly that is unique to humans.

There are three main pathways for the formation of uric acid in the body:

- from purines, which are released during tissue breakdown;

- from purines contained in food;

- from synthetically created purines.

Hyperuricemia can be detected in almost 38% of people, and the level of uric acid in the blood depends on age, gender, nationality, geographical area, level of urbanization, type of diet.

Hyperuricemia can be primary or secondary. There are two ways of developing primary hyperuricemia - metabolic and excretory. The first is associated with a significant intake of purines in the body and their enhanced formation. The increased synthesis of uric acid, characteristic of NAD, may be due to various enzyme defects, the main of which are:

- lack of glutaminase, which transforms glutamine into glutamic acid and ammonia;

- deficiency ofansferase, which provides the synthesis of purine bases (hypoxanthine and guanine) and nucleotides (inosine monophosphate and guanosine monophosphate);

- hypoproduction of uricase, which converts uric acid into more diluted allantoin;

- an excess of phosphoribosyl pyrophosphate synthetase, which catalyzes the synthesis of phosphoribosyl pyrophosphate from ATP and ribose-5-phosphate;

hyperactivity of xanthine oxidase, which oxidizes hypoxanthine to xanthine and uric acid.

Clinic, diagnostics

Currently, NAD is regarded as an enzyme-deficient condition characterized by:

- increased excitability and rapid exhaustion of the nervous system at all levels of reception with the presence of a dominant focus of congestive excitation in the hypothalamic-diencephalic region;

- deficiency of liver enzymes (glucose-6-phosphatase, hypoxanthine-guanine-phosphoribosyl pyrophosphate synthetase);

- low acetylating ability of acetylcoenzyme A due to a deficiency of oxalic acid, which is necessary for the involvement of acetylcoenzyme A in the Krebs cycle;

- violation of the mechanism of reuse of uric and lactic acids;

- violation of fat and carbohydrate metabolism;

- violation of the endocrine regulation of metabolism.

Children with NAD immediately after birth are characterized by increased excitability, emotional lability, sleep disturbance, fearfulness. Aerophagia and pylorospasm are possible. By the age of one, they usually noticeably lag behind their peers in mass. Neuropsychic development, on the contrary, is ahead of age norms. Children quickly master speech, show curiosity, interest in the environment, remember well and retell what they hear, but often show stubbornness and negativism in their behavior. Starting from the age of 2-3 years, they have equivalents of gouty attacks and crises in the form of transient nocturnal pain in the joints, spastic abdominal pain, biliary tract and stomach dyskinesia, odor intolerance, other types of idiosyncrasy, migraine, acetonemic crises. Sometimes there is persistent subfebrile condition. Tics, choreic and tic-like hyperkinesis, affective convulsions, logoneurosis, enuresis are possible. Respiratory and skin allergic manifestations are often noted in the form of atopic bronchial asthma, atopic dermatitis, urticaria, Quincke's edema, and at the age of up to 1 year, allergic skin lesions are extremely rare and appear, as a rule, after 2-3 years. In the pathogenesis of skin syndrome, not only allergic, but also paraallergic (non-immune) reactions are important, due to the release of biologically active substances, a decrease in the synthesis of cyclic nucleotides and a powerful inhibitory effect of uric acid on adenylcyclase. One of the typical manifestations of NAD is saluria with predominant uraturia. Salt excretion is periodically observed simultaneously with dysuria not associated with infection. However, it is possible to develop pyelonephritis, which often joins with nephrolithiasis. In children of prepubertal and pubertal age, an asthenoneurotic or psychasthenic type of accentuation is often detected. Girls show hysterical character traits. Neurasthenia predominates among neuroses. Vegetovascular dysfunction often proceeds according to the hyperkinetic type.

The most pronounced manifestation of metabolic disorders in children with NAD, requiring intensive medical care, is the acetone crisis. Its development can be facilitated by many factors that, in conditions of increased excitability of the nervous system, have a stressful effect: fear, pain, conflict, hyperinsolation, physical or psycho-emotional stress, a change in the microsocial environment, nutritional errors (high content of proteins and fats) and even positive emotions "in excess ". Increased excitability of the vegetative centers of the hypothalamus, which occurs with NAD, under the influence of stress factors causes increased lipolysis and ketogenesis, resulting in the formation of a large number of ketone bodies. This causes irritation of the vomiting center of the brain stem, which causes vomiting.

Acetonemic crises occur suddenly or after precursors (aura), which include anorexia, lethargy, agitation, migraine-like headache, nausea, abdominal pain mainly in the umbilical region, acholic stools, and the smell of acetone from the mouth.

The clinical picture of the acetone crisis:

- repeated or indomitable vomiting within 1-5 days (an attempt to drink or feed a child provokes vomiting);

- dehydration and intoxication (pallor of the skin with a characteristic blush, physical inactivity, muscle hypotension);

- anxiety and agitation at the beginning of the crisis are replaced by lethargy, weakness, drowsiness, in rare cases, symptoms of meningism and convulsions are possible;

- hemodynamic disorders (hypovolemia, weakening of heart tones, tachycardia, arrhythmia);

- spastic abdominal syndrome (cramping or persistent abdominal pain, nausea, stool retention);

- an increase in the liver by 1-2 cm, which persists for 5-7 days after the relief of the crisis;

- an increase in body temperature to 37.5-38.5 ° C;

- the presence in the urine, vomit, exhaled air of acetone, in the blood - an increased concentration of ketone bodies;

- hypochloremia, metabolic acidosis, hypoglycemia, hypercholesterolemia, beta-lipoproteinemia;

- in the peripheral blood, moderate leukocytosis, neutrophilia, a moderate increase in ESR.

Diagnostics

Diagnosis of AS is based on the study of anamnesis, analysis of complaints, clinical symptoms and the results of certain instrumental and laboratory examination methods. It is necessary to establish the nature of the AS: primary or secondary. The diagnosis should contain a breakdown of the main syndromes that predetermine the severity of the child's condition (dehydration, acidosis, hypovolemia, etc.).

Diagnostic criteria for the syndrome of cyclic acetonemic vomiting (primary AS) are defined by international consensus (1994).

Required Criteria:

- repeated, severe, isolated episodes of vomiting;

— various duration intervals of normal health between episodes;

- the duration of episodes of vomiting from several hours to a day;

- negative laboratory, radiological and endoscopic examination results, which could explain the etiology of vomiting, as a manifestation of the pathology of the digestive tract.

Additional criteria:

- vomiting is characterized by stereotypy, and each episode is similar to the previous one in time, intensity and duration;

- attacks of vomiting can end spontaneously and without treatment;

- associated symptoms include nausea, abdominal pain, headache, weakness, photophobia, lethargy;

- associated signs include fever, pallor, diarrhea, dehydration, excessive salivation and social maladaptation;

Vomit often contains bile, mucus and blood. Hematemesis is often the result of retrograde prolapse of the cardial part of the stomach through the gastroesophageal sphincter (i.e., propulsive gastropathy), as in the classic Mallory-Weiss syndrome.

Differential diagnosis of primary AS

It is necessary to determine whether there is a primary AS or a secondary one. Exceptions required:

- diabetic ketoacidosis (determination of the level of glycemia);

- acute surgical pathology of the gastrointestinal tract;

– neurosurgical pathology (MRI, CT of the brain);

- infectious pathology (clinical picture, hyperleukocytosis, elevated ESR);

- poisoning.

Treatment

The treatment of acetonemic syndrome can be divided into two stages: the relief of the acetonemic crisis and the implementation of measures in the interictal period aimed at preventing relapses.

Relief of acetone crisis

The objectives and directions of treatment of AS in children can be formulated as follows:

1) the diet is assigned to all patients. It should contain easily digestible carbohydrates, be enriched with liquid, limit the intake of fats;

2) the appointment of prokinetics (dommperidone, metoclopramide), enzymes and cofactors of carbohydrate metabolism (thiamine, cocarboxylase, pyridoxine) contributes to an earlier restoration of food tolerance and normalization of carbohydrate and fat metabolism;

3) infusion therapy should:

- quickly eliminate hypovolemia and deficiency of extracellular fluid in order to improve perfusion and microcirculation;

4) in cases of moderate ketosis (urine acetone up to "++"), which is not accompanied by significant dehydration, water-electrolyte disorders and uncontrolled vomiting, diet therapy and oral rehydration are indicated in combination with the use of prokinetics in age doses and etiotropic therapy of the underlying disease.

With the initial symptoms of an acetone crisis or its precursors, it is advisable to cleanse and rinse the intestines with a 1-2% sodium bicarbonate solution and give the child every 10-15 minutes to drink sweet tea with lemon, non-carbonated alkaline mineral water (Luzhanskaya, Borjomi, etc.), 1-2% sodium bicarbonate solution, combined solutions for oral rehydration. Food should contain easily digestible carbohydrates and a minimum amount of fat (liquid semolina or oatmeal, mashed potatoes, milk, baked apples). Drug therapy includes antispasmodics (drotaverine for children from 1 to 6 years old - 10-20 mg 2-3 times a day, school-age children - 20-40 mg 2-3 times a day; papaverine bromide (after 5 years of age - 50 -100 mg/day); enterosorbents (in age dosage).Due to the delay in stool in patients, the use of diosmectin is not advisable.

In the case of the development of an acetone crisis, accompanied by repeated or indomitable vomiting, treatment is aimed at correcting acidosis, ketosis, dehydration and dyselectrolytemia. It is advisable to re-cleanse the intestines, and then rinse it with 1-2% sodium bicarbonate solution 1-2 times a day.

Indications for the appointment of infusion therapy:

1. Persistent and repeated vomiting that does not stop after the appointment of prokinetics.

2. Presence of moderate (up to 10% of body weight) and/or severe (up to 15% of body weight) dehydration.

3. The presence of decompensated metabolic acidosis with an increased anion gap.

4. The presence of hemodynamic and microcirculatory disorders.

5. Signs of disorders of consciousness (sopor, ketoacidotic coma).

The presence of anatomical and functional difficulties for oral rehydration (malformations of the facial skeleton and oral cavity), neurological disorders (bulbar and pseudobulbar disorders).

Before starting infusion therapy, it is necessary to ensure reliable venous access (mainly peripheral), using Venflon-type catheters or analogues, to determine hemodynamic parameters, acid-base and water-electrolyte states.

The main tasks for starting infusion therapy are:

- in the correction of hypoglycemia, if it exists;

- elimination of hypovolemia;

- restoration of satisfactory microcirculation.

As infusion solutions, a 5-10% glucose solution with insulin and crystalloid sodium-containing solutions (0.9% sodium chloride solution, Ringer's solution) are used in a ratio of 1: 1 or 2: 1, taking into account the indicators of water-electrolyte metabolism. The total volume of fluid administered is 50-60 ml/kg/day. Reopoliglyukin (10-20 mg/kg) is used to combat hypovolemia and peripheral hypoperfusion. In complex infusion therapy, cocarboxylase is used (50-100 mg / day), 5% ascorbic acid solution (2-3 ml / day). With hypokalemia - correction of the level of potassium (potassium chloride 5% solution 1-3 ml / kg in 100 ml of 5% glucose solution intravenously).

Given the available data regarding the limited ability of the most common crystalloid solutions (saline and glucose solutions) to quickly and effectively eliminate ketosis and its pathophysiological consequences, there are serious theoretical and practical prerequisites for the use of sugar alcohol solutions as alternative means of treating ketotic conditions. The main difference between sugar alcohols (sorbitol, xylitol) is the peculiarities of their metabolism, namely its independence from insulin, and a significantly greater antiketogenic effect.

If the child is willing to drink enough liquid, parenteral infusion solutions can be completely or partially replaced by oral rehydration, which is carried out in combination drugs. With persistent indomitable vomiting, the appointment of metoclopramide parenterally is indicated (for children under 6 years of age, a single dose of 0.1 mg / kg, for children from 6 to 14 years old - 0.5-1.0 ml). Given the possible undesirable side effects from the nervous system (dizziness, extrapyramidal disorders, convulsions), the introduction of metoclopramide more than 1-2 times is not recommended.

With severe abdominal spastic syndrome, antispasmodics are administered parenterally (papaverine, platifillin, drotaverine in an age dosage). If the child is excited, restless, hyperesthesia is expressed, tranquilizers are used - diazepam preparations in middle-aged dosages. After stopping vomiting, it is necessary to give the child a sufficient amount of liquid: dried fruit compote, sweet fruit juices, tea with lemon, low-mineralized alkaline mineral waters. A diet with a sharp restriction of fats, proteins and other ketogenic foods is shown.

Therapeutic measures in the interictal period

Activities in the interictal period are aimed at preventing the recurrence of acetonemic crises and include a number of areas, the main of which is therapeutic nutrition.

Diet therapy for NAD is aimed at:

- to limit the use of foods rich in purines;

- increased excretion of uric acid by the kidneys due to increased diuresis;

— decrease in excitability of the autonomic nervous system;

- Promoting alkalization of urine;

- elimination of food allergens and allergenic substances.

- proteins (purines) contribute to the endogenous formation of uric acid;

- fats negatively affect the excretion of urates from the body;

- Carbohydrates have a sensitizing effect.

However, given the high need of the child's body for plastic material, it is dangerous to reduce the proportion of animal protein in the diet with NAD, although it is necessary to limit the intake as much as possible:

- meat of young animals, poultry and offal (kidneys, heart, liver, lungs, brain, black and liver sausage), as they contain a large amount of purines. Preference is given to the meat of adult animals and birds (beef, lean pork, rabbit, chicken, turkey) in boiled form;

- legumes (peas, soybeans, beans, beans);

- some types of fish (sprats, sardines, sprat, cod, pike perch, pike);

- mushrooms (porcini mushroom);

- salt, because it retains fluid in the tissues and prevents the excretion of uric acid compounds through the kidneys.

Jelly, sauces, meat and fish broths should be excluded from the diet, because. 50% of purines, when boiled, go into the broth. You should not abuse products that have a stimulating effect on the nervous system (coffee, cocoa, strong tea, spicy snacks, spices). Even small amounts of alcohol can impair uric acid excretion, and low levels of the enzyme alcohol dehydrogenase in children with NAD increase the risk of alcohol dependence.

- milk and dairy products;

- vegetables (potatoes, white cabbage, cucumbers, carrots, tomatoes);

- fruits, berries (apples, except Antonovka, watermelon, grapes, apricots, peaches, pears, plums, cherries, oranges);

- hazelnuts and walnuts;

- flour products;

- cereals (except oatmeal and polished rice);

- sugar and honey;

- products enriched with niacin, retinol, riboflavin and vitamin C;

- a large amount of liquid (up to 1.5-2.5 liters depending on age) in the form of citrus and citrate mixtures, carrot drinks, mint and linden teas, vegetable, berry and fruit juices, decoctions of wild rose and berries, alkaline mineral waters. Low-mineralized mineral waters act diuretically, stimulate glomerular filtration processes, and normalize water-salt metabolism. Mineral waters are prescribed at the rate of 3-5 ml / kg for admission three times a day for a month, 3-4 courses per year. Alkalinization of urine increases the solubility of uric acid in the urine and prevents the formation of urate stones. For the same purpose, vegetables and fruits are consumed. Their positive effect lies in the fact that they contain a large amount of potassium ions, which have a diuretic effect and increase the excretion of urates in the urine.

Treatment of AS in the interictal period is carried out in courses, at least 2 times a year, usually in the off-season. Hepatoprotectors are prescribed. With frequent and severe acetonemic crises, ursodeoxycholic acid derivatives are prescribed for the purpose of prevention. In addition to hepatoprotectors, the function of hepatocytes is optimized by lipotropic drugs, which are recommended to be taken 1-2 times a year. With a decrease in the exocrine function of the pancreas, treatment with pancreatic enzyme preparations is carried out for 1-1.5 months until the coprogram parameters are completely normalized. For the treatment of saluria, a decoction of juniper fruits, horsetail extract, decoction and infusion of lingonberry leaves are used. Shown are sedatives from medicinal plants: soothing tea, decoction of valerian root, decoction of hawthorn fruits and flowers, passionflower extract, and Pavlov's mixture. The duration of the use of sedatives is determined by the presence of a syndrome of increased neuro-reflex excitability.

Children with NAD must follow certain rules on the regimen at all times. First of all - a sufficient stay in the fresh air, regular, strictly dosed physical activity (do not overwork), mandatory water procedures (swimming, contrast showers, dousing), prolonged sleep (at least 8 hours). Hyperinsolation should be avoided. It is advisable to reduce the time of watching TV and working with a computer. Due to the restriction of many products in the diet of children, it is recommended to conduct vitamin therapy courses in the winter-spring period. Sanatorium-and-spa treatment is indicated in the conditions of a drinking balneological resort.


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Gout and other disorders of purine metabolism

William N. Kelly, Thomas D. Palilla ( William N. Kelley , Thomas D . Patella

Pathophysiology of hyperuricemia.Classification. Hyperuricemia refers to biochemical signs and serves as a necessary condition for the development of gout. The concentration of uric acid in body fluids is determined by the ratio of the rates of its production and elimination. It is formed during the oxidation of purine bases, which can be of both exogenous and endogenous origin. Approximately 2/3 of uric acid is excreted in the urine (300-600 mg/day), and about 1/3 - through the gastrointestinal tract, where it is eventually destroyed by bacteria. Hyperuricemia may be due to an increased rate of uric acid production, decreased renal excretion, or both.

Hyperuricemia and gout can be divided into metabolic and renal. With metabolic hyperuricemia, the production of uric acid is increased, and with hyperuricemia of renal origin, its excretion by the kidneys is reduced. It is not always possible to clearly distinguish between metabolic and renal types of hyperuricemia. With careful examination in a large number of patients with gout, both mechanisms of development of hyperuricemia can be detected. In these cases, the condition is classified according to the predominant component: renal or metabolic. This classification applies primarily to those cases where gout or hyperuricemia are the main manifestations of the disease, i.e. when gout is not secondary to another acquired disease and does not represent a subordinate symptom of a congenital defect that initially causes some other serious disease, not gout. Sometimes primary gout has a specific genetic basis. Secondary hyperuricemia or secondary gout are cases when they develop as symptoms of another disease or as a result of taking certain pharmacological agents.

Hyperproduction of uric acid. Uric acid overproduction, by definition, means excretion of more than 600 mg/day after following a purine-restricted diet for 5 days. These cases seem to account for less than 10% of all cases. The patient has accelerated synthesis of purines de novo or increased circulation of these compounds. In order to imagine the main mechanisms of the corresponding disorders, it is necessary to analyze the scheme of purine metabolism.

Purine nucleotides - adenyl, inosinic and guanic acids (AMP, IMP and GMP, respectively) - are the end products of purine biosynthesis. They can be synthesized in one of two ways: either directly from purine bases, i.e. HMP from guanine, IMP from hypoxanthine and AMP from adenine, or de novo , starting with non-purine precursors and going through a series of steps to form IMP, which serves as a common intermediate purine nucleotide. Inosinic acid can be converted to either AMP or GMP. Once purine nucleotides are formed, they are used to synthesize nucleic acids, adenosine triphosphate (ATP), cyclic AMP, cyclic GMP, and some cofactors.

Various purine compounds break down to monophosphates of purine nucleotides. Guanic acid is converted via guanosine, guanine xanthine to uric acid, IMF decomposes via inosine, hypoxanthine and xanthine to the same uric acid, and AMP can be deaminated into IMP and further catabolized via inosine to uric acid or converted to inosine by an alternative pathway with intermediate formation of adenosine .

Despite the fact that the regulation of purine metabolism is quite complex, the main determinant of the rate of uric acid synthesis in humans is, apparently, the intracellular concentration of 5-phosphoribosyl-1-pyrophosphate (FRPP). As a rule, with an increase in the level of FRPP in the cell, the synthesis of uric acid increases, with a decrease in its level, it decreases. Despite some exceptions, this is the case in most cases.

Excess production of uric acid in a small number of adult patients is a primary or secondary manifestation of an inborn metabolic disorder. Hyperuricemia and gout may be the primary manifestation of partial deficiency of hypoxanthine-guanine phosphoribosyltransferase or increased activity of FRPP synthetase. In Lesch-Nyhan syndrome, the almost complete deficiency of hypoxanthinguanine phosphoribosyltransferase causes secondary hyperuricemia. These serious congenital anomalies are discussed in more detail below.

For the mentioned congenital metabolic disorders (deficiency of hypoxanthinguanine phosphoribosyltransferase and excessive activity of FRPP synthetase), less than 15% of all cases of primary hyperuricemia due to increased production of uric acid are determined. The reason for the increase in its production in most patients remains unclear.

Secondary hyperuricemia associated with increased production of uric acid can be associated with many causes. In some patients, increased excretion of uric acid is due, as in primary gout, to the acceleration of purine biosynthesis. de novo . In patients with glucose-6-phosphatase deficiency (glycogen storage disease type I), the production of uric acid is constantly increased, as well as the biosynthesis of purines is accelerated. de novo . The overproduction of uric acid in this enzyme abnormality is due to a number of mechanisms. Acceleration of purine synthesis de novo may partly be the result of accelerated FRPF synthesis. In addition, an increase in the excretion of uric acid contributes to the accelerated breakdown of purine nucleotides. Both of these mechanisms are triggered by a lack of glucose as an energy source, and uric acid production can be reduced by permanent correction of the hypoglycemia that is typical of this disease.

In the majority of patients with secondary hyperuricemia due to excessive production of uric acid, the main violation is, obviously, the acceleration of the circulation of nucleic acids. Increased bone marrow activity or a shortening of the life cycle of cells in other tissues, accompanied by accelerated turnover of nucleic acids, is characteristic of many diseases, including myeloproliferative and lymphoproliferative diseases, multiple myeloma, secondary polycythemia, pernicious anemia, some hemoglobinopathies, thalassemia, other hemolytic anemias, infectious mononucleosis and a number of carcinoma. Accelerated circulation of nucleic acids, in turn, leads to hyperuricemia, hyperuricaciduria and a compensatory increase in the rate of purine biosynthesis. de novo.

Decreased excretion. In a large number of patients with gout, this rate of uric acid excretion is achieved only at a plasma urate level of 10–20 mg/l above normal. This pathology is most pronounced in patients with normal production of uric acid and is absent in most cases of its hyperproduction.

Urate excretion depends on glomerular filtration, tubular reabsorption and secretion. Uric acid appears to be completely filtered in the glomerulus and reabsorbed in the proximal tubule (i.e., undergoes presecretory reabsorption). In the underlying segments of the proximal tubule, it is secreted, and in the second site of reabsorption - in the distal proximal tubule - it is once again subjected to partial reabsorption (post-secretory reabsorption). Despite the fact that some of it can be reabsorbed in both the ascending limb of the loop of Henle and the collecting duct, these two sites are considered less important from a quantitative point of view. Attempts to determine more precisely the localization and nature of these latter sites and to quantify their role in the transport of uric acid in a healthy or sick person, as a rule, have been unsuccessful.

Theoretically, impaired renal excretion of uric acid in most patients with gout could be due to: 1) a decrease in the filtration rate; 2) increased reabsorption or 3) decreased secretion rate. There are no indisputable data on the role of any of these mechanisms as the main defect; it is likely that all three factors are present in patients with gout.

Many cases of secondary hyperuricemia and gout can also be considered the result of a decrease in renal excretion of uric acid. A decrease in the glomerular filtration rate leads to a decrease in the filtration load of uric acid and, thereby, to hyperuricemia; in patients with kidney pathology, this is why hyperuricemia develops. In some kidney diseases (polycystic and lead nephropathy), other factors, such as reduced secretion of uric acid, have been postulated. Gout rarely complicates secondary hyperuricemia due to kidney disease.

One of the most important causes of secondary hyperuricemia is diuretic treatment. The decrease in the volume of circulating plasma caused by them leads to an increase in tubular reabsorption of uric acid, as well as to a decrease in its filtration. With hyperuricemia associated with the pathogenesis of acute gouty arthritis, some progress has been made, questions regarding the factors that determine the spontaneous cessation of an acute attack, and the effect of colchicine, still await answer.

Treatment. Treatment for gout involves: 1) if possible, quick and careful relief of an acute attack; 2) prevention of recurrence of acute gouty arthritis; 3) prevention or regression of complications of the disease caused by the deposition of monosubstituted sodium urate crystals in the joints, kidneys and other tissues; 4) prevention or regression of concomitant symptoms such as obesity, hypertriglyceridemia or hypertension; 5) prevention of the formation of uric acid kidney stones.

Treatment for an acute attack of gout. In acute gouty arthritis, anti-inflammatory treatment is performed. The most commonly used is colchicine. It is prescribed for oral administration, usually at a dose of 0.5 mg every hour or 1 mg every 2 hours, and treatment is continued until: 1) the patient's condition is relieved; 2) there will be no adverse reactions from the gastrointestinal tract, or 3) the total dose of the drug will not reach 6 mg against the background of no effect. Colchicine is most effective if treatment is started soon after symptoms appear. In the first 12 hours of treatment, the condition improves significantly in more than 75% of patients. However, in 80% of patients, the drug causes adverse reactions from the gastrointestinal tract, which may occur before clinical improvement or simultaneously with it. When administered orally, the maximum plasma level of colchicine is reached after about 2 hours. Therefore, it can be assumed that its administration at 1.0 mg every 2 hours is less likely to cause the accumulation of a toxic dose before the manifestation of a therapeutic effect. Since, however, the therapeutic effect is related to the level of colchicine in leukocytes and not in plasma, the effectiveness of the treatment regimen requires further evaluation.

With intravenous administration of colchicine, side effects from the gastrointestinal tract do not occur, and the patient's condition improves faster. After a single injection, the level of the drug in leukocytes increases, remaining constant for 24 hours, and can be determined even after 10 days. 2 mg should be administered intravenously as an initial dose, and then, if necessary, repeated administration of 1 mg twice with an interval of 6 hours. Special precautions should be taken when colchicine is administered intravenously. It has an irritating effect and, if it enters the tissues surrounding the vessel, can cause severe pain and necrosis. It is important to remember that the intravenous route of administration requires care and that the drug should be diluted in 5-10 volumes of normal saline, and the infusion should be continued for at least 5 minutes. Both orally and parenterally, colchicine can depress bone marrow function and cause alopecia, hepatic cell failure, mental depression, convulsions, ascending paralysis, respiratory depression, and death. Toxic effects are more likely in patients with liver, bone marrow, or kidney disease, and in those receiving maintenance doses of colchicine. In all cases, the dose of the drug must be reduced. It should not be given to patients with neutropenia.

Other anti-inflammatory drugs, including indomethacin, phenylbutazone, naproxen, and fenoprofen, are also effective in acute gouty arthritis.

Indomethacin can be administered orally at a dose of 75 mg, after which every 6 hours the patient should receive 50 mg; treatment with these doses continues the next day after the symptoms disappear, then the dose is reduced to 50 mg every 8 hours (three times) and to 25 mg every 8 hours (also three times). Side effects of indomethacin include gastrointestinal disturbances, sodium retention in the body, and central nervous system symptoms. Although these doses may cause side effects in up to 60% of patients, indomethacin is usually better tolerated than colchicine and is probably the drug of choice in acute gouty arthritis. To increase the effectiveness of treatment and reduce the manifestations of pathology, the patient should be warned that taking anti-inflammatory drugs should be started at the first sensations of pain. Drugs that stimulate the excretion of uric acid, and allopurinol in an acute attack of gout are ineffective.

In acute gout, especially when colchicine and non-steroidal anti-inflammatory drugs are contraindicated or ineffective, systemic or local (i.e., intra-articular) administration of glucocorticoids is beneficial. For systemic administration, whether oral or intravenous, moderate doses should be administered over several days, as the concentration of glucocorticoids decreases rapidly and their action ceases. Intra-articular administration of a long-acting steroid drug (eg, triamcinolone hexacetonide at a dose of 15-30 mg) can stop an attack of monoarthritis or bursitis within 24-36 hours. This treatment is especially useful when it is impossible to use the standard drug regimen.

Prevention. After stopping an acute attack, a number of measures are used to reduce the likelihood of relapse. These include: 1) daily prophylactic colchicine or indomethacin; 2) controlled weight loss in obese patients; 3) elimination of known triggers, such as large amounts of alcohol or purine-rich foods; 4) the use of antihyperuricemic drugs.

Daily administration of small doses of colchicine effectively prevents the development of subsequent acute attacks. Colchicine at a daily dose of 1-2 mg is effective in almost 1/4 of patients with gout and ineffective in about 5% of patients. In addition, this treatment program is safe and has virtually no side effects. However, if the concentration of urate in the serum is not maintained within the normal range, then the patient will be spared only from acute arthritis, and not from other manifestations of gout. Maintenance treatment with colchicine is especially indicated during the first 2 years after starting antihyperuricemic drugs.

Prevention or stimulation of the regression of gouty deposits of monosubstituted sodium urate in tissues. Antihyperuricemic agents are quite effective in reducing serum urate concentration, so they should be used in patients with: 1) one attack of acute gouty arthritis or more; 2) one gouty deposit or more; 3) uric acid nephrolithiasis. The purpose of their use is to maintain serum urate levels below 70 mg/l; i.e., in the minimum concentration at which urate saturates the extracellular fluid. This level can be achieved with drugs that increase renal excretion of uric acid, or by reducing the production of this acid. Antihyperuricemic agents usually do not have an anti-inflammatory effect. Uricosuric drugs reduce serum urate levels by increasing its renal excretion. Despite the fact that a large number of substances have this property, probenecid and sulfinpyrazone are the most effective used in the United States. Probenecid is usually prescribed at an initial dose of 250 mg twice daily. In a few weeks, it is increased to provide a significant decrease in the concentration of urate in the serum. In half of the patients, this can be achieved with a total dose of 1 g / day; the maximum dose should not exceed 3.0 g / day. Since the half-life of probenecid is 6-12 hours, it should be taken in equal doses 2-4 times a day. The main side effects include hypersensitivity, skin rash and gastrointestinal symptoms. Despite rare cases of toxic effects, these adverse reactions force almost 1/3 of patients to stop treatment.

Sulfinpyrazone is a metabolite of phenylbutazone, devoid of anti-inflammatory action. They begin treatment at a dose of 50 mg twice a day, gradually increasing the dose to a maintenance level of 300-400 mg / day for 3-4 times. The maximum effective daily dose is 800 mg. Side effects are similar to those of probenecid, although the incidence of bone marrow toxicity may be higher. Approximately 25% of patients stop taking the drug for one reason or another.

Probenecid and sulfinpyrazone are effective in most cases of hyperuricemia and gout. In addition to drug intolerance, treatment failure may be due to a violation of their regimen, the simultaneous use of salicylates, or impaired renal function. Acetylsalicylic acid (aspirin) at any dose blocks the uricosuric effect of probenecid and sulfinpyrazone. They become less effective at creatinine clearance below 80 ml/min and stop at 30 ml/min.

With a negative balance of urate due to treatment with uricosuric drugs, the concentration of urate in the serum decreases, and the excretion of uric acid in the urine exceeds the initial level. Continued treatment causes the mobilization and excretion of excess urate, its amount in the serum decreases, and the excretion of uric acid in the urine almost reaches the initial values. A transient increase in its excretion, usually lasting only a few days, can cause the formation of kidney stones in 1/10 of patients. In order to avoid this complication, uricosuric agents should be started with low doses, gradually increasing them. Maintaining increased urination with adequate hydration and alkalinization of urine by oral administration of sodium bicarbonate alone or together with acetazolamide reduces the likelihood of stone formation. The ideal candidate for treatment with uricosuric agents is a patient under the age of 60, on a normal diet, with normal renal function and uric acid excretion of less than 700 mg/day, with no history of kidney stones.

Hyperuricemia can also be corrected with allopurinol, which reduces the synthesis of uric acid. It inhibits xanthine oxidase, which catalyzesoxidation of hypoxanthine to xanthine and xanthine to uric acid. Despite the fact that the half-life of allopurinol in the body is only 2-3 hours, it is converted mainly to hydroxypurinol, which is an equally effective xanthine oxidase inhibitor, but with a half-life of 18-30 hours. In most patients, a dose of 300 mg / day is effective. Due to the long half-life of the main metabolite of allopurinol, it can be administered once a day. Since oxypurinol is excreted primarily in the urine, its half-life is prolonged in renal failure. In this regard, with a pronounced impairment of kidney function, the dose of allopurinol should be halved.

Serious side effects of allopurinol include gastrointestinal dysfunction, skin rashes, fever, toxic epidermal necrolysis, alopecia, bone marrow depression, hepatitis, jaundice, and vasculitis. The overall frequency of side effects reaches 20%; they often develop in renal failure. Only in 5% of patients, their severity makes it necessary to stop treatment with allopurinol. When prescribing it, drug-drug interactions should be taken into account, as it increases the half-lives of mercaptopurine and azathioprine and increases the toxicity of cyclophosphamide.

Allopurinol is preferred over uricosuric agents for: 1) increased (more than 700 mg/day with a general diet) excretion of uric acid in the urine; 2) impaired renal function with creatinine clearance less than 80 ml/min; 3) gouty deposits in the joints, regardless of kidney function; 4) uric acid nephrolithiasis; 6) gout, not amenable to the effects of uricosuric drugs due to their inefficiency or intolerance. In rare cases of failure of each drug used alone, allopurinol can be used simultaneously with any uricosuric agent. This does not require a change in the dose of drugs and is usually accompanied by a decrease in serum urate levels.

No matter how rapid and pronounced the decrease in serum urate levels, acute gouty arthritis may develop during treatment. In other words, the initiation of treatment with any anti-hyperuricemic drug may trigger an acute attack. In addition, with large gouty deposits, even against the background of a decrease in the severity of hyperuricemia for a year or more, relapses of attacks may occur. In this regard, before starting anti-hyperuricemic agents, it is advisable to start prophylactic colchicine and continue it until the serum urate level is within the normal range for at least a year or until all arthritic deposits have dissolved. Patients should be aware of the possibility of exacerbations in the early period of treatment. Most patients with large deposits in the joints and / or kidney failure should sharply limit the intake of purines with food.

Prevention of acute uric acid nephropathy and treatment of patients. In acute uric acid nephropathy, intensive treatment should be started immediately. Urination should first be increased with large water loads and diuretics, such as furosemide. Urine is alkalized so that uric acid is converted into more soluble monosodium urate. Alkalinization is achieved with sodium bicarbonate alone or in combination with acetazolamide. Allopurinol should also be administered to reduce the formation of uric acid. Its initial dose in these cases is 8 mg/kg once daily. After 3-4 days, if renal failure persists, the dose is reduced to 100-200 mg / day. For uric acid kidney stones, the treatment is the same as for uric acid nephropathy. In most cases, it is sufficient to combine allopurinol only with the consumption of large amounts of liquid.

Management of patients with hyperuricemia.Examination of patients with hyperuricemia is aimed at: 1) finding out its cause, which may indicate another serious disease; 2) assessment of damage to tissues and organs and its degree; 3) identification of concomitant disorders. In practice, all these tasks are solved simultaneously, since the decision regarding the significance of hyperuricemia and treatment depends on the answer to all these questions.

The most important in hyperuricemia are the results of a urine test for uric acid. With indications of a history of urolithiasis, an overview picture of the abdominal cavity and intravenous pyelography are shown. If kidney stones are found, testing for uric acid and other components may be helpful. In the pathology of the joints, it is advisable to examine the synovial fluid and produce x-rays of the joints. If there is a history of lead exposure, it may be necessary to determine lead excretion in urine after calcium-EDTA infusion to diagnose gout associated with lead poisoning. If increased production of uric acid is suspected, determination of the activity of hypoxanthine-guanine phosphoribosyltransferase and FRPP synthetase in erythrocytes may be indicated.

Management of patients with asymptomatic hyperuricemia. The question of the need to treat patients with asymptomatic hyperuricemia does not have a clear answer. As a rule, treatment is not required, unless: 1) the patient makes no complaints; 2) no family history of gout, nephrolithiasis, or renal failure; or 3) uric acid excretion is not too high (more than 1100 mg/day).

Other disorders of purine metabolism, accompanied by hyperuricemia and gout. Deficiency of hypoxanthine-guanine phosphoribosyltransferase. Hypoxanthineguanine phosphoribosyltransferase catalyzes the conversion of hypoxanthine to inosic acid and guanine to guanosine. The donor of phosphoribosyl is FRPP. Insufficiency of hypoxanthileads to a decrease in the consumption of FRPP, which accumulates in concentrations greater than normal. Excess FRPP accelerates purine biosynthesis de novo and consequently increases the production of uric acid.

Lesch-Nyhan syndrome is an X-linked disorder. A characteristic biochemical disorder in it is a pronounced deficiency of hypoxanthine-guanine phosphoribosyltransferase. Patients have hyperuricemia and excessive hyperproduction of uric acid. In addition, they develop peculiar neurological disorders characterized by self-mutilation, choreoathetosis, muscle spasticity, and growth and mental retardation. The frequency of this disease is estimated as 1:100,000 newborns.

Approximately 0.5-1.0% of adult patients with gout with excessive production of uric acid reveal a partial deficiency of hypoxanthine-guanine phosphoribosyltransferase. Usually they have gouty arthritis at a young age (15-30 years), a high frequency of uric acid nephrolithiasis (75%), sometimes some neurological symptoms join, including dysarthria, hyperreflexia, impaired coordination and / or mental retardation. The disease is inherited as an X-linked trait, so it is passed on to men from female carriers.

The enzyme whose deficiency causes this disease (hypoxanthine-guanine phosphoribosyltransferase) is of significant interest to geneticists. With the possible exception of the globin gene family, the hypoxanthinguanine phosphoribosyltransferase locus is the most studied human single gene.

Human hypoxanthine guanine phosphoribosyltransferase was purified to a homogeneous state, and its amino acid sequence was determined. Normally, its relative molecular weight is 2470, and the subunit consists of 217 amino acid residues. The enzyme is a tetramer consisting of four identical subunits. There are also four variant forms of hypoxanthine-guanine phosphoribosyltransferase. In each of them, the replacement of one amino acid leads either to the loss of the catalytic properties of the protein or to a decrease in the constant concentration of the enzyme due to a decrease in the synthesis or acceleration of the decay of the mutant protein.

A DNA sequence complementary to messenger RNA (mRNA) that codes for gyloxanthinguanine phosphoribosyltransferase has been cloned and deciphered. As a molecular probe, this sequence was used to identify the state of carriage in women at risk, in whom conventional methods could not be detected as carriers. The human gene was transferred into a mouse using a bone marrow transplant infected with a vector retrovirus. The expression of human hypoxanthine-guanine phosphoribosyltransferase in the thus treated mouse was determined with certainty. Recently, a transgenic line of mice has also been obtained, in which the human enzyme is expressed in the same tissues as in humans.

The concomitant biochemical anomalies that cause the pronounced neurological manifestations of the Lesch-Nyhan syndrome have not been sufficiently deciphered. Post-mortem examination of the brains of patients showed signs of a specific defect in the central dopaminergic pathways, especially in the basal ganglia and nucleus accumbens . Relevant data in vivo were obtained using positron emission tomography (PET) performed in patients with hypoxanthine-guanine phosphoribosyltransferase deficiency. In most patients examined by this method, a violation of the metabolism of 2 "-fluoro-deoxyglucose in the caudate nucleus was revealed. The relationship between the pathology of the dopaminergic nervous system and the violation of purine metabolism remains unclear.

Hyperuricemia due to partial or complete deficiency of hypoxanthine-guanine phosphoribosyltransferase successfully responds to the action of allopurinol, a xanthine oxidase inhibitor. In this case, a small number of patients form xanthine stones, but most of them with kidney stones and gout are cured. There are no specific treatments for neurological disorders in Lesch-Nyhan syndrome.

Variants of FRPP synthetase. Several families have been identified whose members had increased activity of the FRPP synthetase enzyme. All three known types of the mutant enzyme have increased activity, which leads to an increase in the intracellular concentration of FRPP, an acceleration of purine biosynthesis, and an increase in uric acid excretion. This disease is also inherited as an X-linked trait. As with partial deficiency of hypoxanthine-guanine phosphoribosyltransferase, gout usually develops in this pathology in the second or third 10 years of life and uric acid stones often form. In several children, increased activity of FRPP synthetase was combined with nervous deafness.

Other disorders of purine metabolism.Deficiency of adenine phosphoribosyltransferase. Adenine phosphoribosyl transferase catalyses the conversion of adenine to AMP. The first person who was found to be deficient in this enzyme was heterozygous for this defect and had no clinical symptoms. Then it was found that heterozygosity for this trait is quite widespread, probably with a frequency of 1:100. Currently, 11 homozygotes for this enzyme deficiency have been identified, in which kidney stones consisted of 2,8-dioxyadenine. Because of the chemical similarity, 2,8-dioxyadenin is easily confused with uric acid, so these patients were initially erroneously diagnosed with uric acid nephrolithiasis.

Xanthine oxidase deficiency . Xanthine oxidase catalyzes the oxidation of hypoxanthine to xanthine, xanthine to uric acid, and adenine to 2,8-dioxyadenine. Xanthinuria, the first congenital disorder of purine metabolism, deciphered at the enzymatic level, is due to a deficiency of xanthine oxidase. As a result, patients with xanthinuria show hypouricemia and hypouricaciduria, as well as increased urinary excretion of oxypurines-hypoxanthine and xanthine. Half of the patients do not complain, and in 1/3 xanthine stones form in the urinary tract. Several patients developed myopathy and three developed polyarthritis, which could be a manifestation of crystal-induced synovitis. In the development of each of the symptoms, xanthine precipitation is of great importance.

In four patients, congenital deficiency of xanthine oxidase was combined with congenital deficiency of sulfate oxidase. The clinical picture in newborns was dominated by severe neurological pathology, which is typical for isolated sulfate oxidase deficiency. Despite the fact that the deficiency of the molybdate cofactor necessary for the functioning of both enzymes was postulated as the main defect, treatment with ammonium molybdate was ineffective. A patient who was completely on parenteral nutrition developed a disease simulating a combined deficiency of xanthine oxidase and sulfate oxidase. After the treatment with ammonium molybdate, the function of enzymes was completely normalized, which led to clinical recovery.

Myoadenylate deaminase deficiency . Myoadenylate deaminase, an isoenzyme of adenylate deaminase, is found only in skeletal muscle. The enzyme catalyses the conversion of adenylate (AMP) to inosic acid (IMF). This reaction is an integral part of the purine nucleotide cycle and, apparently, is important for maintaining the processes of production and utilization of energy in skeletal muscle.

Deficiency of this enzyme is determined only in skeletal muscle. Most patients experience myalgia, muscle spasms, and fatigue during exercise. Approximately 1/3 of patients complain of muscle weakness even in the absence of exercise. Some patients do not complain.

The disease usually manifests itself in childhood and adolescence. Clinical symptoms with it are the same as with metabolic myopathy. Creatinine kinase levels are elevated in less than half of the cases. Electromyographic studies and routine histology of muscle biopsy specimens reveal nonspecific changes. Presumably, adenylate deaminase deficiency can be diagnosed based on the results of the performance test of the ischemic forearm. In patients with a deficiency of this enzyme, ammonia production is reduced because AMP deamination is blocked. The diagnosis should be confirmed by direct determination of AMP-deaminase activity in a skeletal muscle biopsy, since reduced ammonia production during work is also characteristic of other myopathies. The disease progresses slowly and in most cases leads to some decrease in performance. There is no effective specific therapy.

Adenyl succinase deficiency . Patients with adenylsuccinase deficiency are mentally retarded and often suffer from autism. In addition, they suffer from convulsive seizures, their psychomotor development is delayed, and a number of movement disorders are noted. Urinary excretion of succinylaminoimidazole carboxamidriboside and succinyladenosine is increased. The diagnosis is established by detecting a partial or complete absence of enzyme activity in the liver, kidneys, or skeletal muscles. In lymphocytes and fibroblasts, its partial insufficiency is determined. The prognosis is unknown and no specific treatment has been developed.

T.P. Harrison. principles of internal medicine.Translation d.m.s. A. V. Suchkova, Ph.D. N. N. Zavadenko, Ph.D. D. G. Katkovsky

Violations and their causes in alphabetical order:

violation of purine metabolism -

Purine metabolism - a set of processes for the synthesis and decay of purine nucleotides. Purine nucleotides consist of a residue of a nitrogenous purine base, a ribose (deoxyribose) carbohydrate linked by a b-glycosidic bond to the nitrogen atom of the purine base, and one or more phosphoric acid residues attached by an ester bond to the carbon atom of the carbohydrate component.

What diseases cause a violation of purine metabolism:

The most important disorders of purine metabolism include excessive formation and accumulation of uric acid, for example, in gout and Lesch-Nyhan syndrome.

The latter is based on a hereditary deficiency of the enzyme hypoxanthine phosphatidyltransferase, as a result of which free purines are not reused, but are oxidized into uric acid.

In children with the Lesha-Nyhan syndrome, inflammatory and dystrophic changes are noted. caused by the deposition of uric acid crystals in the tissues: the disease is characterized by a delay in mental and physical development.

Violation of purine metabolism is accompanied by a violation of fat (lipid) metabolism. Therefore, in many patients, body weight increases, atherosclerosis of the aorta and coronary arteries progresses, coronary heart disease develops, and blood pressure rises steadily.

Gout is often accompanied by diabetes mellitus, cholelithiasis, and significant changes occur in the kidneys.

Attacks of gout provoke alcohol intake, hypothermia, physical and mental overstrain, usually begin at night with severe pain.

Which doctors to contact if there is a violation of purine metabolism:

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Exchange of deoxyuridyl nucleotides

Deoxyuridyl nucleotides are intermediates in the synthesis of thymidyl nucleotides. dUTP is easily recognized by DNA polymerases and can be used for DNA synthesis instead of dTTP. When uracil replicates in the DNA structure, it forms a complementary pair with adenine, so that the information recorded on the DNA is not lost. However, dUMP can occur in the DNA structure by spontaneous deamination of dCMP. In this case, a mutation occurs during replication, since the complementary base of cytosine is guanine, and not adenine.

A simple mechanism operates to prevent the incorporation of uridine nucleotides into DNA in cells. The enzyme dUTPase converts dUTP (a substrate of DNA polymerase) into dUMP (not a substrate of DNA polymerase), which is used for the synthesis of thymidyl nucleotides, since dUMP is converted first to dTMP and then to dTTP.

The end product of the breakdown of purine nucleotides, uric acid, is characterized by low solubility in water; its sodium salt has a higher solubility. The form in which uric acid is found in biological fluids (blood, urine, cerebrospinal fluid) depends on the pH of that fluid. The pK value for the N9 proton is 5.75, and for the N-l proton it is 10.3. This means that under physiological conditions, that is, at normal pH of physiological fluids, both uric acid itself and its monosodium salt (sodium urate) can be detected. In liquids with a pH below 5.75, the main molecular form is uric acid. At pH 5.75, the acid and its salt are present in equimolar amounts. Above pH 5.75, the dominant form is the sodium salt of uric acid.

Purine metabolism disorders include hyperuricemia, hypouricemia, and immunodeficiency diseases.

A very high concentration of uric acid in the blood leads to a fairly common group of diseases called gout. The frequency of gout depends on the country and is about 3/1000. Gout is a group of pathological conditions associated with markedly elevated blood levels of urate (normally 3-7 mg/100 ml). Hyperuricemia does not always show any symptoms but, in some people, contributes to the deposition of sodium urate crystals in the joints and tissues. In addition to the severe pain that accompanies an exacerbation, repeated attacks lead to tissue destruction and severe arthritis-like disorders. The term gout should be limited to hyperuricemia with the presence of such gouty deposits.

Below is a table indicating the possible causes of disorders of purine nucleotide metabolism

Along with other pathologies, a violation of purine metabolism is also considered a serious disease, the treatment of which should be given attention. First of all, these are malfunctions in the metabolism of useful substances that provoke the occurrence of other diseases, such as gout, nephropathy or kidney failure.

As a rule, there is a violation of purine metabolism in children, but adults are also susceptible to this pathology. Only usually patients in adulthood face a number of concomitant diseases and complications.

General information

Violation of purine metabolism according to ICD-10 has the code E79. Usually this disease is chronic in nature and is directly related to the deposition of acid salts in the tissues of the kidneys and joints. Symptoms of disorders of purine metabolism are quite specific and appear as recurring exacerbations of arthritis, accompanied by pain.

An undiagnosed and untreated problem in time can lead to more serious consequences: for example, the onset of urolithiasis and kidney failure. All therapeutic measures in such a situation are usually aimed at stopping unpleasant symptoms, reducing the severity of the clinical picture, preventing the development of complications and normalizing the metabolism of useful substances.

Causes of pathology

A prerequisite for the development of the disease is the excessive formation of purine bases or their too slow excretion with uric acid.

The primary form of pathology is explained by hereditary predisposition. But the secondary type of the disease can be associated with the regular intake of diuretics, anti-inflammatory drugs and other medicines.

Purine metabolism disorders provoke:

  • alcoholic drinks;
  • severe hypothermia;
  • some pharmaceuticals;
  • products containing relevant education;
  • pathologies of an infectious nature;
  • psycho-emotional and physical stress.

Symptoms

Signs of disorders of purine metabolism resemble typical manifestations of metabolic failures. Pathology is characterized by an increased level of creatinine kinase, which appears in almost all patients. Other nonspecific signs of the disease can be detected using an electromyographic examination.

In patients with disorders of purine metabolism, an extremely low production of ammonia is observed, due to which working capacity is significantly reduced and appetite is almost completely absent. Patients feel general malaise, lethargy, depression. In some cases, pronounced weakness develops.

Children suffering from disorders of purine metabolism for a long time often remain mentally underdeveloped and have an increased tendency to autism. In more rare cases, small and adult patients experience seizures resembling epileptic seizures, as well as convulsions. Among other things, the psychomotor development of a sick person slows down or even stops.

Peculiarities

The most striking disorders of purine metabolism include excessive formation and further accumulation of uric acid, which is observed in gout and Lesch-Nyhan syndrome. The latter lies in the hereditary lack of a certain enzyme, which leads to the non-use of re-released purines. As a result, they are oxidized, transforming into uric acid.

Diagnostics

Identification of the disease is extremely difficult and does not always give an accurate result, since this pathology has many features similar to other disorders in homeostasis. However, with a long-term observation of the patient's condition and his analyzes in general terms, it is quite possible to detect failures in purine metabolism and the reasons for its occurrence.

The diagnosis can be made on the basis, first of all, of the complete absence of indicators of the functioning of renal enzymes, active substances of the liver and skeletal muscles. With the help of laboratory tests, partial insufficiency can be detected in lymphocytes and fibroblasts.

A special treatment that would be aimed at eliminating enzyme dysfunction has not yet been developed, so you can only rely on complex therapy.

Treatment

Purine metabolism disorders require complex treatment, which is based primarily on a strict diet, including foods low in uric acid, and drug therapy.

Pharmacological methods include several stages:

  • balance and normalization of metabolic processes with the help of fortification;
  • establishment of metabolic acidosis and control of the acidic environment in the urine;
  • establishment and constant maintenance of a normal level of hyperlipidemia;
  • control and normalization of the patient's blood pressure during the day;
  • therapy of possible complications of pathology.

Treatment of consequences

Gout is a disorder of purine metabolism that has not been diagnosed and treated in time. These diseases are very closely related. That is why the signs and treatment of gout are not much different from those with metabolic failures. In general, the treatment of this pathology comes down to the correction of purine metabolism. For this, the patient is recommended:

  • limit physical activity during exacerbations;
  • adherence to a certain diet;
  • drinking regimen, including 2 liters of water daily;
  • the use of local compresses using "Dimexide";
  • use of prescribed doses of non-steroidal anti-inflammatory drugs.

Treatment of disorders of purine metabolism can be carried out both in stationary conditions and at home. However, the latter option is acceptable only after consultation with a specialist and confirmation of the diagnosis.

Medical therapy

Basic treatment is based on the long-term use of drugs that normalize the amount of uric acid in the blood. Medicines can only be used during remission. Depending on the effect, there are several varieties of recommended drugs:

  • drugs that reduce the production of uric acid, for example, "Allopurinol";
  • medicines containing etebenecid - increase the rate of excretion of uric acid from the body;
  • mixed drugs.

Long-term drug therapy is appropriate for frequent attacks, a pronounced clinical picture of the disease, the formation of tophi and kidney injury.

In the intervals of remission, patients are also shown a variety of physiotherapy procedures: massage, paraffin baths, ultrasound.

In almost all pathology treatment regimens, doctors mention the observance of a certain diet. A special diet helps the patient to effectively eliminate the negative effects of metabolic disorders. Usually, the first complications that a balanced diet effectively copes with are a disorder in fat metabolism. Against the background of this pathology, the patient is rapidly gaining weight, and sometimes faces atherosclerosis, coronary heart disease, as well as a steady increase in blood pressure.

In all the situations described, experts prescribe diets to patients in which the amount of purine-rich foods is limited or completely absent. These include: mushrooms, meat, legumes, fish. In addition, patients are shown fasting days with a vegetable, dairy or fruit menu.

It is worth saying that the diet for violations of purine metabolism should be used for quite a long time. The patient's diet provides for fractional meals 4-5 times a day.

The menu also excludes purines, has certain restrictions regarding salt, proteins, fats and carbohydrates. The energy value of the daily diet should range from 2700-2800 calories. The daily menu provides for the consumption of 80 g of proteins, 90 g of fat, 400 g of carbohydrates.

  • lean meats and fish;
  • dairy components;
  • bread from the first grade of flour;
  • all kinds of cereals;
  • vegetables and fruits in any form.

Should be excluded:

  • fatty fish and meat;
  • raspberries;
  • strong tea and coffee;
  • chocolate;
  • cocoa powder;
  • legumes;
  • cranberries;
  • sorrel.

A variety of cooking oils are also prohibited.

Subject to a properly selected diet and other components of complex treatment, the patient feels significant relief in just a few weeks.

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